Copolymers of lysine and polyethylene glycol: a new family of functionalized drug carriers

Abstract

Poly(PEG-Lys), a new, water-soluble poly(ether urethane), derived from L-lysine and poly(ethylene glycol) was investigated as a precursor for the preparation of polymeric drug conjugates. To facilitate a wide variety of coupling chemistries, the pendent carboxyl groups of poly(PEG-Lys) were converted to other reactive functional groups (amino, hydroxyl, active ester, and aldehyde) in high yield. These reactive pendent chains were then used as anchors for the covalent attachment of penicillin V and cephradine, two clinically used antimicrobial agents. Coupling to the carrier was achieved in good yields and the chemical versatility of this system was demonstrated by the preparation of conjugates having antibiotic ligands linked via biostable or biodegradable linkages to the carrier, either directly or via a spacer. Conjugate 4, poly(PEG-Lys-penicillin V ester), was obtained by linking penicillin V to the polymer backbone via hydrolytically labile ester bonds. This conjugate exhibited activity similar to that of the parent drug against three clinically important strains of bacteria. Drug activity coincided with the release of the drug from the carrier. Hydrolytically stable cephradine-containing conjugates were prepared by three different coupling methods but showed no antibiotic activity. 14C-labeled poly(PEG-Lys) was injected into mice and its biodistribution was monitored for 48 h. The carrier showed no preferential uptake by liver, spleen, or kidney. No signs of acute toxicity were evident in mice or rats when poly(PEG-Lys) was administered iv and ip at doses up to 10 g/kg. These results indicate that poly(PEG-Lys) is a promising precursor for the preparation of soluble drug conjugates.

Click Chemistry, A Powerful Tool for Pharmaceutical Sciences

“…As one of the potential solutions to these challenges, a linear multifunctional PEG design has been proposed as a polymeric drug carrier (63). The concept is to join short telechelic PEGs with tri-functional linkers.…”

“…With this method vinyl monomer synthesis is no longer necessary. While several approaches have been made to synthesize the linear multifunctional PEG construct (63)(64)(65)(66), further improvements are desperately needed. In particular, the chemistry that joins the short PEG segments should be much more efficient, and tolerant of pendent functionality conjugation.…”

Polymeric pharmaceutical forms - the forms of the future

“…An important parameter of polymer-pharmaceutical conjugates is the drug release from the polymer carrier. A wide range of polymers have wide application, such as polyethylene glycols (1,15,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), polyesters (33), polyether-polyesters (34), peptides (35,36), polyglutamic acid (37,38), hyaluronic acid (39)(40)(41), polyphosphoesters (32,42,43).…”

EPR Assembly of Microgel for FRET Imaging of Breast Cancer

“…It would be relevant to mention that the copolymers reported above are derived from Nathan et al (1993) and had been prepared earlier in our laboratory by using N-α-t-Boc-L-aspartic acid (Pooyan et al 2002) instead of tritylmercaptosuccinic acid (Qiu et al 2003). The scheme of synthesis is shown Figure 5 depicts an alternative synthesis of the amino functionality via the thiol-containing PEG copolymer.…”